Cyclic amino acids and derivatives thereof useful as pharmaceutical agents

ABSTRACT

The invention is a novel series of cyclic amino acids which are useful in the treatment of epilepsy, faintness attacks, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, gastrointestinal disorders such as irritable bowel syndrome (IBS), and inflammation, especially arthritis. A pharmaceutical composition containing a compound of the invention as well as methods of preparing the compounds and novel intermediates useful in the preparation of the final compounds are included.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional Application, which claims the benefitof priority to U.S. Ser. No. 10/448,834 filed May 30, 2003, now U.S.Pat. No. 6,921,835, which is a continuation of U.S. Ser. No. 09/485,382filed Feb. 8, 2000, now U.S. Pat. No. 6,635,673 which is a 371 ofPCT/US98/19876 filed Sep. 23, 1998, which claims priority from U.S.Provisional Application No. 60/063,644 filed Oct. 27, 1997, and U.S.Provisional Application No. 60/097,685 filed Aug. 24, 1998, the contentsof each of which are hereby incorporated herein by reference.

BACKGROUND OF THE INVENTION

Compounds of formula

wherein R₁ is hydrogen or a lower alkyl radical and n is 4, 5, or 6 areknown in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No.4,087,544. The uses disclosed are: protective effect against crampinduced by thiosemicarbazide; protective action against cardiazolecramp; the cerebral diseases, epilepsy, faintness attacks, hypokinesia,and cranial traumas; and improvement in cerebral functions. Thecompounds are useful in geriatric patients. The patents are herebyincorporated by reference.

SUMMARY OF THE INVENTION

The compounds of the invention are those of formulas 1 and 1A

wherein R to R¹⁴ are as defined below.

The compounds of the invention and their pharmaceutically acceptablesalts and the prodrugs of the compounds, are useful in the treatment ofepilepsy, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, depression, anxiety, panic, pain,neuropathological disorders, gastrointestinal disorders such asirritable bowel syndrome (IBS), and inflammation, especially arthritis.

The invention is also a pharmaceutical composition of a compound offormulas 1 and 1A.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the instant invention and their pharmaceuticallyacceptable salts are as defined by formulas 1 and 1A

or a pharmaceutically acceptable salt thereof wherein:

-   R is hydrogen or a lower alkyl;-   R¹ to R¹⁴ are each independently selected from hydrogen, straight or    branched alkyl of from 1 to 6 carbons, phenyl, benzyl, fluorine,    chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl,    trifluoromethyl, —CO₂H, —CO₂R¹⁵, —CH₂CO₂H, —CH₂CO₂R¹⁵, —OR¹⁵ wherein    R¹⁵ is a straight or branched alkyl of from 1 to 6 carbons, phenyl,    or benzyl, and R¹ to R⁸ are not simultaneously hydrogen.

Preferred compounds of the invention are those of Formula I wherein R¹to R¹⁴ are selected from hydrogen, methyl, ethyl, propyl, isopropyl,butyl straight or branched, phenyl, or benzyl.

More preferred compounds are those of Formula I wherein R¹ to R¹⁴ areselected from hydrogen, methyl, ethyl, or benzyl.

The most preferred compounds are selected from:

-   (1α,3α,4α)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid;-   (1α,3α,4α)-(1-Aminomethyl-3,4-diethyl-cyclopentyl)-acetic acid;-   (1α,3α,4α)-(1-Aminomethyl-3,4-diisopropyl-cyclopentyl)-acetic acid;-   [1S-(1α,3α,4α)]-(1-Aminomethyl-3-ethyl-4-methyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4α)]-(1-Aminomethyl-3-ethyl-4-methyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4α)]-(1-Aminomethyl-3-isopropyl-4-methyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4α)]-(1-Aminomethyl-3-isopropyl-4-methyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4α)]-(1-Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4α)]-(1-Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4α)]-(1-Aminomethyl-3-tert-butyl-4-methyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4α)]-(1-Aminomethyl-3-tert-butyl-4-methyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4α)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4α)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4α)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4α)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl)-acetic    acid;-   (1α,3α,4α)-(1-Aminomethyl-3,4-di-tert-butyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4α)]-(1-Aminomethyl-3-methyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4α)]-(1-Aminomethyl-3-methyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4α)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclopentyl)-acetic    acid;-   [1R—(1α,3α,4α)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclopentyl)-acetic    acid;-   (1S-cis)-(1-Aminomethyl-3-methyl-cyclopentyl)-acetic acid;-   (1S-cis)-(1-Aminomethyl-3-ethyl-cyclopentyl)-acetic acid;-   (1S-cis)-(1-Aminomethyl-3-isopropyl-cyclopentyl)-acetic acid;-   (1S-cis)-(1-Aminomethyl-3-tert-butyl-cyclopentyl)-acetic acid;-   (1S-cis)-(1-Aminomethyl-3-phenyl-cyclopentyl)-acetic acid;-   (1S-cis)-(1-Aminomethyl-3-benzyl-cyclopentyl)-acetic acid;-   (1R-cis)-(1-Aminomethyl-3-methyl-cyclopentyl)-acetic acid;-   (1R-cis)-(1-Aminomethyl-3-eth yl-cyclopentyl)-acetic acid;-   (1R-cis)-(1-Aminomethyl-3-isopropyl-cyclopentyl)-acetic acid;-   (1R-cis)-(1-Aminomethyl-3-tert-butyl-cyclopentyl)-acetic acid;-   (1R-cis)-(1-Aminomethyl-3-phenyl-cyclopentyl)-acetic acid;-   (1R-cis)-(1-Aminomethyl-3-benzyl-cyclopentyl)-acetic acid;-   (S)-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-acetic acid;-   (S)-(1-Aminomethyl-3,3-diethyl-cyclopentyl)-acetic acid;-   (1-Aminomethyl-3,3,4,4-tetramethyl-cyclopentyl)-acetic acid;-   (1-Aminomethyl-3,3,4,4-tetra ethyl-cyclopentyl)-acetic acid;-   (1α,3β,4β)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid;-   (1α,3β,4β)-(1-Aminomethyl-3,4-diethyl-cyclopentyl)-acetic acid;-   (1α,3β,4β)-(1-Aminomethyl-3,4-diisopropyl-cyclopentyl)-acetic acid;-   [1R-(1α,3β,4β)]-(1-Aminomethyl-3-ethyl-4-methyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4β)]-(1-Aminomethyl-3-ethyl-4-methyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4β)]-(1-Aminomethyl-3-isopropyl-4-methyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4β)]-(1-Aminomethyl-3-isopropyl-4-methyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4β)]-(1-Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4β)]-(1-Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4β)]-(1-Aminomethyl-3-tert-butyl-4-methyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4β)]-(1-Aminomethyl-3-tert-butyl-4-methyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4β)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4β)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4β)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4β)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl)-acetic    acid;-   (1α,3β,4β)-(1-Aminomethyl-3,4-di-tert-butyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4β)]-(1-Aminomethyl-3-methyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4β)]-(1-Aminomethyl-3-methyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4β)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4β)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclopentyl)-acetic    acid;-   (1R-trans)-(1-Aminomethyl-3-methyl-cyclopentyl)-acetic acid;-   (1R-trans)-(1-Aminomethyl-3-ethyl-cyclopentyl)-acetic acid;-   (1R-trans)-(1-Aminomethyl-3-isopropyl-cyclopentyl)-acetic acid;-   (1R-trans)-(1-Aminomethyl-3-tert-butyl-cyclopentyl)-acetic acid;-   (1R-trans)-(1-Aminomethyl-3-phenyl-cyclopentyl)-acetic acid;-   (1R-trans)-(1-Aminomethyl-3-benzyl-cyclopentyl)-acetic acid;-   (1S-trans)-(1-Aminomethyl-3-methyl-cyclopentyl)-acetic acid;-   (1S-trans)-(1-Aminomethyl-3-ethyl-cyclopentyl)-acetic acid;-   (1S-trans)-(1-Aminomethyl-3-isopropyl-cyclopentyl)-acetic acid;-   (1S-trans)-(1-Aminomethyl-3-tert-butyl-cyclopentyl)-acetic acid;-   (1S-trans)-(1-Aminomethyl-3-phenyl-cyclopentyl)-acetic acid;-   (1S-trans)-(1-Aminomethyl-3-benzyl-cyclopentyl)-acetic acid;-   (R)-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-acetic acid;-   (R)-(1-Aminomethyl-3,3-diethyl-cyclopentyl)-acetic acid;-   cis-(1-Aminomethyl-3-methyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-ethyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-isopropyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-tert-butyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-phenyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-benzyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-methyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-ethyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-isopropyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-tert-butyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-phenyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-benzyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-ethyl-3-methyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-isopropyl-3-methyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-tert-butyl-3-methyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-methyl-3-phenyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-benzyl-3-methyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-ethyl-3-methyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-isopropyl-3-methyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-tert-butyl-3-methyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-methyl-3-phenyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-benzyl-3-methyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-ethyl-3-isopropyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-tert-butyl-3-ethyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-ethyl-3-phenyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-benzyl-3-ethyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-ethyl-3-isopropyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-tert-butyl-3-ethyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-ethyl-3-phenyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-benzyl-3-ethyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-tert-butyl-3-isopropyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-isopropyl-3-phenyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-benzyl-3-isopropyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-tert-butyl-3-phenyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-benzyl-3-tert-butyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-tert-butyl-3-isopropyl-cyclobutyl)-acetic    acid;-   trans-(1-Aminomethyl-3-isopropyl-3-phenyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-benzyl-3-isopropyl-cyclobutyl)-acetic acid;-   trans-(1-Aminomethyl-3-tert-butyl-3-phenyl-cyclobutyl)-acetic acid;-   cis-(1-Aminomethyl-3-benzyl-3-tert-butyl-cyclobutyl)-acetic acid;-   (1-Aminomethyl-3,3-dimethyl-cyclobutyl)-acetic acid;-   (1-Aminomethyl-3,3-diethyl-cyclobutyl)-acetic acid;-   (1-Aminomethyl-3,3-diisopropyl-cyclobutyl)-acetic acid;-   (1-Aminomethyl-3,3-di-tert-butyl-cyclobutyl)-acetic acid;-   (1-Aminomethyl-3,3-diphenyl-cyclobutyl)-acetic acid;-   (1-Aminomethyl-3,3-dibenzyl-cyclobutyl)-acetic acid;-   (1-Aminomethyl-2,2,4,4-tetramethyl-cyclobutyl)-acetic acid;-   (1-Aminomethyl-2,2,3,3,4,4-hexamethyl-cyclobutyl)-acetic acid;-   (R)-(1-Aminomethyl-2,2-dimethyl-cyclobutyl)-acetic acid;-   (S)-(1-Aminomethyl-2,2-dimethyl-cyclobutyl)-acetic acid;-   (1R-cis)-(1-Aminomethyl-2-methyl-cyclobutyl)-acetic acid;-   [1R-(1α,2α,3α)]-(1-Aminomethyl-2,3-dimethyl-cyclobutyl)-acetic acid;-   (1α,2α,4α)-(1-Aminomethyl-2,4-dimethyl-cyclobutyl)-acetic acid;-   [1R-(1α,2α,3β)]-(1-Aminomethyl-2,3-dimethyl-cyclobutyl)-acetic acid;-   (1α,2α,4β)-(1-Aminomethyl-2,4-dimethyl-cyclobutyl)-acetic acid;-   (1S-trans)-(1-Aminomethyl-2-methyl-cyclobutyl)-acetic acid;-   [1S-(1α,2β,3β)]-(1-Aminomethyl-2,3-dimethyl-cyclobutyl)-acetic acid;-   (1α,2β,4β)-(1-Aminomethyl-2,4-dimethyl-cyclobutyl)-acetic acid;-   [1S-(1α,2β,3α)]-(1-Aminomethyl-2,3-dimethyl-cyclobutyl)-acetic acid;-   (1α,2β,4α)-(1-Aminomethyl-2,4-dimethyl-cyclobutyl)-acetic acid;-   (1R-trans)-(1-Aminomethyl-2-methyl-cyclobutyl)-acetic acid;-   [1R-(1α,2β,3β)]-(1-Aminomethyl-2,3-dimethyl-cyclobutyl)-acetic acid;-   [1R-(1α,2β,4β)]-(1-Aminomethyl-2-ethyl-4-methyl-cyclobutyl)-acetic    acid;-   [1R-(1α,2β,3α)]-(1-Aminomethyl-2,3-dimethyl-cyclobutyl)-acetic acid;-   (1α,2β,4α)-(1-Aminomethyl-2,4-dimethyl-cyclobutyl)-acetic acid;-   (1S-cis)-(1-Aminomethyl-2-methyl-cyclobutyl)-acetic acid;-   [1S-(1α,2α,3α)]-(1-Aminomethyl-2,3-dimethyl-cyclobutyl)-acetic acid;-   [1S-(1α,2α,3α)]-(1-Aminomethyl-2,4-dimethyl-cyclobutyl)-acetic acid;-   [1S-(1α,2β,3α)]-(1-Aminomethyl-2,3-dimethyl-cyclobutyl)-acetic acid;-   (1α,2α,4β)-(1-Aminomethyl-2,4-dimethyl-cyclobutyl)-acetic acid;-   (3S,4S)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid;-   (3R,4R)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid;-   (3S,4S))-(1-Aminomethyl-3,4-diethyl-cyclopentyl)-acetic acid;-   (3R,4R)-(1-Aminomethyl-3,4-diethyl-cyclopentyl)-acetic acid;-   (3S,4S)-(1-Aminomethyl-3,4-diisopropyl-cyclopentyl)-acetic acid;-   (3R,4R)-(1-Aminomethyl-3,4-diisopropyl-cyclopentyl)-acetic acid;-   (3S,4S)-(1-Aminomethyl-3,4-di-tert-butyl-cyclopentyl)-acetic acid;-   (3R,4R)-(1-Aminomethyl-3,4-di-tert-butyl-cyclopentyl)-acetic acid;-   (3S,4S)-(1-Aminomethyl-3,4-diphenyl-cyclopentyl)-acetic acid;-   (3R,4R)-(1-Aminomethyl-3,4-diphenyl-cyclopentyl)-acetic acid;-   (3S,4S)-(1-Aminomethyl-3,4-dibenzyl-cyclopentyl)-acetic acid;-   (3R,4R)-(1-Aminomethyl-3,4-dibenzyl-cyclopentyl)-acetic acid;-   [1S-(1α,3α,4β)]-(1-Aminomethyl-3-methyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4α)]-(1-Aminomethyl-3-methyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4β)]-(1-Aminomethyl-3-methyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4α)]-(1-Aminomethyl-3-methyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4β)]-(1-Aminomethyl-3-methyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4α)]-(1-Aminomethyl-3-methyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4β)]-(1-Aminomethyl-3-methyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4α)]-(1-Aminomethyl-3-methyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4β)]-(1-Aminomethyl-3-methyl-4-tert-butyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4α)]-(1-Aminomethyl-3-methyl-4-tert-butyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4β)]-(1-Aminomethyl-3-methyl-4-tert-butyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4β)]-(1-Aminomethyl-3-methyl-4-tert-butyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4β)]-(1-Aminomethyl-3-methyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4α)])-(1-Aminomethyl-3-methyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4β)]-(1-Aminomethyl-3-methyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4α)]-(1-Aminomethyl-3-methyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4β)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4α)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4β)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4α)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4β)]-(1-Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4α)]-(1-Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4β)]-(1-Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4α)]-(1-Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4β)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4α)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4β)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4α)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4β)]-(1-Aminomethyl-3-ethyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4α)]-(1-Aminomethyl-3-ethyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4β)]-(1-Aminomethyl-3-ethyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4α)]-(1-Aminomethyl-3-ethyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4β)]-(1-Aminomethyl-3-benzyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4α)]-(1-Aminomethyl-3-benzyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4β)]-(1-Aminomethyl-3-benzyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4α)]-(1-Aminomethyl-3-benzyl-4-ethyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4β)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4α)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4β)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4α)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4β)]-(1-Aminomethyl-3-isopropyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4α)]-(1-Aminomethyl-3-isopropyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4β)]-(1-Aminomethyl-3-isopropyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4α)]-(1-Aminomethyl-3-isopropyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4β)]-(1-Aminomethyl-3-benzyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4α)]-(1-Aminomethyl-3-benzyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4β)]-(1-Aminomethyl-3-benzyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4α)]-(1-Aminomethyl-3-benzyl-4-isopropyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4β)]-(1-Aminomethyl-3-tert-butyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4α)]-(1-Aminomethyl-3-tert-butyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4β)]-(1-Aminomethyl-3-tert-butyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4α)]-(1-Aminomethyl-3-tert-butyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4β)]-(1-Aminomethyl-3-benzyl-4-tert-butyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4α)]-(1-Aminomethyl-3-benzyl-4-tert-butyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4β)]-(1-Aminomethyl-3-benzyl-4-tert-butyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4α)]-(1-Aminomethyl-3-benzyl-4-tert-butyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3α,4β)]-(1-Aminomethyl-3-benzyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3β,4α)]-(1-Aminomethyl-3-benzyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1R-(1α,3α,4β)]-(1-Aminomethyl-3-benzyl-4-phenyl-cyclopentyl)-acetic    acid;-   [1S-(1α,3β,4α)]-(1-Aminomethyl-3-benzyl-4-phenyl-cyclopentyl)-acetic    acid;-   (1R-cis)-(1-Aminomethyl-2-methyl-cyclopentyl)-acetic acid;-   (1S-cis)-(1-Aminomethyl-2-methyl-cyclopentyl)-acetic acid;-   (1R-trans)-(1-Aminomethyl-2-methyl-cyclopentyl)-acetic acid;-   (1S-trans)-(1-Aminomethyl-2-methyl-cyclopentyl)-acetic acid;-   (R)-(1-Aminomethyl-2,2-dimethyl-cyclopentyl)-acetic acid;-   (S)-(1-Aminomethyl-2,2-dimethyl-cyclopentyl)-acetic acid;-   (1-Aminomethyl-2,2,5,5-tetramethyl-cyclopentyl)-acetic acid;-   (1α,2β,5β)-(1-Aminomethyl-2,5-dimethyl-cyclopentyl)-acetic acid;-   (2R,5R)-(1-Aminomethyl-2,5-dimethyl-cyclopentyl)-acetic acid;-   (2S,5S)-(1-Aminomethyl-2,5-dimethyl-cyclopentyl)-acetic acid;-   (1α,2α,5α)-(1-Aminomethyl-2,5-dimethyl-cyclopentyl)-acetic acid;-   [1R-(1α,2α,3α)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl)-acetic    acid;-   [1R-(1α,2β,3α)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl)-acetic    acid;-   [1R-(1α,2α,3β)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl)-acetic    acid;-   [1R-(1α,2β,3β)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl)-acetic    acid;-   [1S-(1α,2α,3α)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl)-acetic    acid;-   [1S-(1α,2β,3α)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl)-acetic    acid;-   [1S-(1α,2α,3β)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl)-acetic    acid;-   [1S-(1α,2β,3β)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl)-acetic    acid;-   [1R-(1α,2α,4α)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl)-acetic    acid;-   [1S-(1α,2α,4α)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl)-acetic    acid;-   [1R-(1α,2α,4β)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl)-acetic    acid;-   [1S-(1α,2α,4β)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl)-acetic    acid;-   [1R-(1α,2β,4α)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl)-acetic    acid;-   [1S-(1α,2β,4α)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl)-acetic    acid;-   [1R-(1α,2β,4β)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl)-acetic    acid; and-   [1S-(1α,2β,4β)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl)-acetic    acid.

Certain intermediates are useful in the preparation of the compounds ofthe invention:

-   (trans)-(3,4-Dimethyl-cyclopentylidene)-acetic acid ethyl ester;-   (trans)-(3,4-Dimethyl-1-nitromethyl-cyclopentyl)-acetic acid;-   (+)-(trans)-7,8-Dimethyl-2-aza-spiro[4.4]nonane-3-one;-   (1-Nitromethyl-cyclobutyl)-acetic acid ethyl ester;-   (cis/trans)-(3R)-(3-Methyl-1-nitromethyl-cyclopentyl)-acetic acid    ethyl ester;-   (cis/trans)-(7R)-7-Methyl-2-aza-spiro[4.4]nonane-3-one;-   (cis)-(3,4-Dimethyl-cyclopentylidene)-acetic acid ethyl ester;-   (trans)-3,4-Dimethyl-1-nitromethyl-cyclopentyl)-acetic acid ethyl    ester;-   (trans)-7,8-Dimethyl-2-aza-spiro[4.4]nonane-3-one;-   (3-Benzyl-cyclobutylidene)-acetic acid ethyl ester; and-   (cis/trans)-(3-Benzyl-1-nitromethyl-cyclopentyl)-acetic acid ethyl    ester.

The term “lower alkyl” is a straight or branched group of from 1 to 4carbons.

The term “alkyl” is a straight or branched group of from 1 to 6 carbonatoms including but not limited to methyl, ethyl, propyl, n-propyl,isopropyl, butyl, 2-butyl, tert-butyl, pentyl, except as where otherwisestated.

The benzyl and phenyl groups may be unsubstituted or substituted by from1 to 3 substituents selected from hydroxy, carboxy, carboalkoxy,halogen, CF₃, nitro, alkyl, and alkoxy. Preferred are halogens.

Since amino acids are amphoteric, pharmacologically compatible saltswhen R is hydrogen can be salts of appropriate inorganic or organicacids, for example, hydrochloric, sulphuric, phosphoric, acetic, oxalic,lactic, citric, malic, salicylic, malonic, maleic, succinic,methanesulfonic acid, and ascorbic. Starting from correspondinghydroxides or carbonates, salts with alkali metals or alkaline earthmetals, for example, sodium, potassium, magnesium, or calcium areformed. Salts with quaternary ammonium ions can also be prepared with,for example, the tetramethyl-ammonium ion. The carboxyl group of theamino acids can be esterified by known means.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R(D) or S(L)configuration. The present invention includes all enantiomeric andepimeric forms as well as the appropriate mixtures thereof.

Methods and Materials

Animals

Male Sprague-Dawley rats (180–250 g) were obtained from Bantin andKingman, (Hull, U.K.). Animals were housed in groups of 6 to 10 under a12 hour light/dark cycle (lights on at 7 hours, 0 minutes) with food andwater ad libitum.

Carrageenan-Induced Thermal Hyperalgesia in the Rat

Thermal hyperalgesia was assessed using the rat plantar test (UgoBasile, Italy) following a modified method of Hargreaves, et al., 1988.Rats were habituated to the apparatus which consisted of threeindividual perspex boxes on an elevated glass table. A mobile radiantheat source located under the table was focused onto the desired paw andpaw withdrawal latencies (PWL) recorded. PWL were taken 3 times for bothhind paws of each animal, the mean of which represented baselines forright and left hind paws. At least 5 minutes were allowed between eachPWL for an animal. The apparatus was calibrated to give a PWL ofapproximately 10 s. There was an automatic cutoff point of 20 s toprevent tissue damage. After baseline PWLs were determined, animalsreceived an intraplantar injection of carrageenan (100 μL of 20 mg/mL)into the right hind paw. PWLs were reassessed following the sameprotocol as above 2-hour post-carrageenan (this time point representedthe start of peak hyperalgesia) to ascertain that hyperalgesia haddeveloped. Test compounds were administered orally (in a volume of 1mL/kg) at 2.5 hours after carrageenan. PWLs were reassessed at varioustimes after drug administration.

A Model of Anticonvulsant Efficacy and Protocol for DBA2 Test:Prevention of Audiogenic Seizures in DBA/2 Mice

Methods

All procedures were carried out in compliance with the NIH Guide for theCare and Use of Laboratory Animals under a protocol approved by theParke-Davis Animal Use Committee. Male DBA/2 mice, 3 to 4 weeks old,were obtained from Jackson Laboratories, Bar Harbour, Me. Immediatelybefore anticonvulsant testing, mice were placed upon a wire mesh, 4inches square suspended from a steel rod. The square was slowly invertedthrough 180 degrees and mice observed for 30 seconds. Any mouse fallingfrom the wire mesh was scored as ataxic.

Mice were placed into an enclosed acrylic plastic chamber (21 cm height,approximately 30 cm diameter) with a high-frequency speaker (4 cmdiameter) in the center of the top lid. An audio signal generator(Protek model B-810) was used to produce a continuous sinusoidal tonethat was swept linearly in frequency between 8 kHz and 16 kHz once each10 msec. The average sound pressure level (SPL) during stimulation wasapproximately 100 dB at the floor of the chamber. Mice were placedwithin the chamber and allowed to acclimatize for 1 minute. DBA/2 micein the vehicle-treated group responded to the sound stimulus (applieduntil tonic extension occurred, or for a maximum of 60 seconds) with acharacteristic seizure sequence consisting of wild running followed byclonic seizures, and later by tonic extension, and finally byrespiratory arrest and death in 80% or more of the mice. Invehicle-treated mice, the entire sequence of seizures to respiratoryarrest lasts approximately 15 to 20 seconds.

The incidence of all the seizure phases in the drug-treated andvehicle-treated mice was recorded, and the occurrence of tonic seizureswere used for calculating anticonvulsant ED₅₀ values by probit analysis.Mice were used only once for testing at each dose point. Groups of DBA/2mice (n=5–10 per dose) were tested for sound-induced seizure responses 2hours (previously determined time of peak effect) after given drugorally. All drugs in the present study were dissolved in distilled waterand given by oral gavage in a volume of 10 mL/kg of body weight.compounds that are insoluble will be suspended in 1%carboxymethocellulose. Doses are expressed as weight of the active drugmoiety.

Results

The dose-dependent suppression of sound-induced tonic seizures in DBA/2mice was tested, and the corresponding ED₅₀ values are shown in Table 1.

The present results show that the compounds of the invention givenorally cause dose-related anticonvulsant effects in a sound susceptiblestrain (DBA/2) of mice, confirming previous data showing anticonvulsantactivity in other models of experimental epilepsy. The effective dosagesof drugs in this model are lower than those in the maximal electroshocktest, confirming that DBA/2 mice are a sensitive model for detectinganticonvulsant actions.

TABLE 1 Carrageenan Induced Thermal DBA/2 Hyperalgesia in the RatAudiogenic Mouse IC₅₀ (μM) % MPE^(a) 1 hr % MPE^(a) 2 hr % Protected atα₂δ postdose @ postdose @ 1 hr postdose Compound Structure binding site30 mg/kg PO 30 mg/kg PO 30 mg/kg PO(±)-(trans)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-aceticacidhydrochloride

0.034 23 72 100(+)-(trans)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-aceticacidhydrochloride

0.022 109 118 100(−)-(trans)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-aceticacidhydrochloride

1.0 (cis/trans)-(3R)-(1-Aminomethyl-3-methyl-cyclopentyl)-aceticacidhydrochloride

0.088 67 53 100 (trans)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-aceticacidhydrochloride

0.154 −7 −2 100 (1-Aminomethyl-cyclobutyl)-acetic acidhydrochloride

0.598 4 4 20 (2 hour postdose)(cis/trans)-(1-Aminomethyl-3-benzyl-cyclobutyl)-acetic acidhydrochloride

>10 0 0 not tested ^(a)MPE: maximum possible effect - set as baselinevalue prior to treatment with carrageenan.

The radioligand binding assay using [³H]gabapentin and the α₂δ subunitderived from porcine brain tissue was used (“The Novel Anti-convulsantDrug, Gabapentin, Binds to the α₂δ Subunit of a Calcium Channel”, Gee N.et al., J. Biological Chemistry, in press).

The compounds of the invention show good binding affinity to the α₂δsubunit. Gabapentin (Neurontin®) is about 0.10 to 0.12 μM in this assay.Since the compounds of the instant invention also bind to the subunit,they are expected to exhibit pharmacologic properties comparable togabapentin. For example, as agents for convulsions, anxiety, and pain.

The compounds of the invention are related to Neurontin®, a marketeddrug effective in the treatment of epilepsy. Neurontin® is1-(aminomethyl)-cyclohexaneacetic acid of structural formula

The compounds of the invention are also expected to be useful in thetreatment of epilepsy.

The present invention also relates to therapeutic use of the compoundsof the mimetic as agents for neurodegenerative disorders.

Such neurodegenerative disorders are, for example, Alzheimer's disease,Huntington's disease, Parkinson's disease, and Amyotrophic LateralSclerosis.

The present invention also covers treating neurodegenerative disorderstermed acute brain injury. These include but are not limited to: stroke,head trauma, and asphyxia.

Stroke refers to a cerebral vascular disease and may also be referred toas a cerebral vascular accident (CVA) and includes acute thromboembolicstroke. Stroke includes both focal and global ischemia. Also, includedare transient cerebral ischemic attacks and other cerebral vascularproblems accompanied by cerebral ischemia such as in a patientundergoing carotid endarterectomy specifically or other cerebrovascularor vascular surgical procedures in general, or diagnostic vascularprocedures including cerebral angiography and the like.

Other incidents are head trauma, spinal cord trauma, or injury fromgeneral anoxia, hypoxia, hypoglycemia, hypotension as well as similarinjuries seen during procedures from embole, hyperfusion, and hypoxia.

The instant invention would be useful in a range of incidents, forexample, during cardiac bypass surgery, in incidents of intracranialhemorrhage, in perinatal asphyxia, in cardiac arrest, and statusepilepticus.

A skilled physician will be able to determine the appropriate situationin which subjects are susceptible to or at risk of, for example, strokeas well as suffering from stroke for administration by methods of thepresent invention.

The compounds of the invention are also expected to be useful in thetreatment of depression. Depression can be the result of organicdisease, secondary to stress associated with personal loss, oridiopathic in origin. There is a strong tendency for familial occurrenceof some forms of depression suggesting a mechanistic cause for at leastsome forms of depression. The diagnosis of depression is made primarilyby quantification of alterations in patients' mood. These evaluations ofmood are generally performed by a physician or quantified by aneuropsychologist using validated rating scales, such as the HamiltonDepression Rating Scale or the Brief Psychiatric Rating Scale. Numerousother scales have been developed to quantify and measure the degree ofmood alterations in patients with depression, such as insomnia,difficulty with concentration, lack of energy, feelings ofworthlessness, and guilt. The standards for diagnosis of depression aswell as all psychiatric diagnoses are collected in the Diagnostic andStatistical Manual of Mental Disorders (Fourth Edition) referred to asthe DSM-IV-R manual published by the American Psychiatric Association,1994.

GABA is an inhibitory neurotransmitter with the central nervous system.Within the general context of inhibition, it seems that GABA-mimeticswill decrease or inhibit cerebral function and will therefore slowfunction and decrease mood leading to depression.

The compounds of the instant invention may produce an anticonvulsanteffect through the increase of newly created GABA at the synapticjunction. If gabapentin does indeed increase GABA levels or theeffectiveness of GABA at the synaptic junction, then it could beclassified as a GABA-mimetic and might decrease or inhibit cerebralfunction and might, therefore, slow function and decrease mood leadingto depression.

The fact that a GABA agonist or GABA-mimetic might work just theopposite way by increasing mood and thus, be an antidepressant, is a newconcept, different from the prevailing opinion of GABA activityheretofore.

The compounds of the instant invention are also expected to be useful inthe treatment of anxiety and of panic as demonstrated by means ofstandard pharmacological procedures.

Material and Methods

Carrageenin-Induced Hyperalgesia

Nociceptive pressure thresholds were measured in the rat paw pressuretest using an analgesymeter (Randall-Sellitto Method: Randall L. O.,Sellitto J. J., A method for measurement of analgesic activity oninflamed tissue. Arch. Int. Pharmacodyn., 1957;4:409–419). MaleSprague-Dawley rats (70–90 g) were trained on this apparatus before thetest day. Pressure was gradually applied to the hind paw of each rat andnociceptive thresholds were determined as the pressure (g) required toelicit paw withdrawal. A cutoff point of 250 g was used to prevent anytissue damage to the paw. On the test day, two to three baselinemeasurements were taken before animals were administered 100 μL of 2%carrageenin by intraplantar injection into the right hind paw.Nociceptive thresholds were taken again 3 hours after carrageenin toestablish that animals were exhibiting hyperalgesia. Animals were dosedwith either gabapentin (3–300 mg/kg, s.c.), morphine (3 mg/kg, s.c.), orsaline at 3.5 hours after carrageenin and nociceptive thresholds wereexamined at 4, 4.5, and 5 hours post-carrageenin.

Semicarbazide-Induced Tonic Seizures

Tonic seizures in mice are induced by subcutaneous administration ofsemicarbazide (750 mg/kg). The latency to the tonic extension offorepaws is noted. Any mice not convulsing within 2.0 hours aftersemicarbazide are considered protected and given a maximum latency scoreof 120 minutes.

Animals

Male Hooded Lister rats (200–250 g) are obtained from Interfauna(Huntingdon, UK) and male TO mice (20–25 g) are obtained from Bantin andKingman (Hull, UK). Both rodent species are housed in groups of six. TenCommon Marmosets (Callithrix Jacchus) weighing between 280 and 360 g,bred at Manchester University Medical School (Manchester, UK) are housedin pairs. All animals are housed under a 12-hour light/dark cycle(lights on at 07.00 hour) and with food and water ad libitum.

Drug Administration

Drugs are administered either intraperitoneally (IP) or subcutaneously(SC) 40 minutes before the test in a volume of 1 mL/kg for rats andmarmosets and 10 mL/kg for mice.

Mouse Light/Dark Box

The apparatus is an open-topped box, 45 cm long, 27 cm wide, and 27 cmhigh, divided into a small (2/5) and a large (3/5) area by a partitionthat extended 20 cm above the walls (Costall B., et al., Exploration ofmice in a black and white box: validation as a model of anxiety.Pharmacol. Biochem. Behav., 1989; 32: 777–785).

There is a 7.5×7.5 cm opening in the center of the partition at floorlevel. The small compartment is painted black and the large compartmentwhite. The white compartment is illuminated by a 60-W tungsten bulb. Thelaboratory is illuminated by red light. Each mouse is tested by placingit in the center of the white area and allowing it to explore the novelenvironment for 5 minutes. The time spent in the illuminated side ismeasured (Kilfoil T., et al., Effects of anxiolytic and anxiogenic drugson exploratory activity in a simple model of anxiety in mice.Neuropharmacol., 1989; 28: 901–905).

Rat Elevated X-Maze

A standard elevated X-maze (Handley S. L., et al., Effects ofalpha-adrenoceptor agonists and antagonists in a maze-exploration modelof ‘fear’-motivated behavior. Naunyn-Schiedeberg's Arch. Pharmacol.,1984; 327: 1–5) was automated as previously described (Field, et al.,Automation of the rat elevated X-maze test of anxiety. Br. J.Pharmacol., 1991; 102(Suppl): 304P). The animals are placed on thecenter of the X-maze facing one of the open arms. For determininganxiolytic effects the entries and time spent on the end half sectionsof the open arms is measured during the 5-minute test period (Costall,et al., Use of the elevated plus maze to assess anxiolytic potential inthe rat. Br. J. Pharmacol., 1989; 96(Suppl): 312P).

Marmoset Human Threat Test

The total number of body postures exhibited by the animal towards thethreat stimulus (a human standing approximately 0.5 m away from themarmoset cage and staring into the eyes of the marmoset) is recordedduring the 2-minute test period. The body postures scored are slitstares, tail postures, scent marking of the cage/perches, piloerection,retreats, and arching of the back. Each animal is exposed to the threatstimulus twice on the test day before and after drug treatment. Thedifference between the two scores is analyzed using one-way analysis ofvariance followed by Dunnett's t-test. All drug treatments are carriedout SC at least 2 hours after the first (control) threat. Thepretreatment time for each compound is 40 minutes.

Rat Conflict Test

Rats are trained to press levers for food reward in operant chambers.The schedule consists of alternations of four 4-minute unpunishedperiods on variable interval of 30 seconds signaled by chamber lights onand three 3-minute punished periods on fixed ratio 5 (by footshockconcomitant to food delivery) signaled by chamber lights off. The degreeof footshock is adjusted for each rat to obtain approximately 80% to 90%suppression of responding in comparison with unpunished responding. Ratsreceive saline vehicle on training days.

The compounds of the instant invention are also expected to be useful inthe treatment of pain and phobic disorders (Am. J. Pain Manag., 1995; 5:7–9).

The compounds of the instant invention are also expected to be useful intreating the symptoms of manic, acute or chronic, single upside, orrecurring. They are also expected to be useful in treating and/orpreventing bipolar disorder (U.S. Pat. No. 5,510,381).

Models of Irritable Bowel Syndrome

TNBS-Induced Chronic Visceral Allodynia In Rats

Injections of trinitrobenzene sulfonic acid (TNBS) into the colon havebeen found to induce chronic colitis. In humans, digestive disorders areoften associated with visceral pain. In these pathologies, the visceralpain threshold is decreased indicating a visceral hypersensitivity.Consequently, this study was designed to evaluate the effect ofinjection of TNBS into the colon on visceral pain threshold in anexperimental model of colonic distension.

Materials and Methods

Animals and Surgery

Male Sprague-Dawley rats (Janvier, Le Genest-St-Ilse, France) weighing340–400 g are used. The animals are housed 3 per cage in a regulatedenvironment (20±1° C., 50±5% humidity, with light 8:00 am to 8:00 pm).Under anesthesia (ketamine 80 mg/kg i.p; acepromazin 12 mg/kg ip), theinjection of TNBS (50 mg/kg) or saline (1.5 mL/kg) is performed into theproximal colon (1 cm from the cecum). After the surgery, animals areindividually housed in polypropylene cages and kept in a regulatedenvironment (20±1° C., 50±5% humidity, with light 8:00 am to 8:00 pm)during 7 days.

Experimental Procedure

At Day 7 after TNBS administration, a balloon (5–6 cm length) isinserted by anus and kept in position (tip of balloon 5 cm from theanus) by taping the catheter to the base of the tail. The balloon isprogressively inflated by step of 5 mm Hg, from 0 to 75 mm Hg, each stepof inflation lasting 30 seconds. Each cycle of colonic distension iscontrolled by a standard barostat (ABS, St-Die, France). The thresholdcorresponds to the pressure which produced the first abdominalcontraction and the cycle of distension is then discontinued. Thecolonic threshold (pressure expressed in mm Hg) is determined afterperformance of four cycles of distension on the same animal.

Determination of the Activity of the Compound

Data is analyzed by comparing test compound-treated group withTNBS-treated group and control group. Mean and sem are calculated foreach group. The antiallodynic activity of the compound is calculated asfollows:Activity (%)=(group C−group T)/(group A−group T)

-   -   Group C: mean of the colonic threshold in the control group    -   Group T: mean of the colonic threshold in the TNBS-treated group    -   Group A: mean of the colonic threshold in the test        compound-treated group        Statistical Analysis

Statistical significance between each group was determined by using aone-way ANOVA followed by Student's unpaired t-test. Differences wereconsidered statistically significant at p<0.05.

Compounds

TNBS is dissolved in EtOH 30% and injected under a volume of 0.5 mL/rat.TNBS is purchased from Fluka.

Oral administration of the test compound or its vehicle is performed 1hour before the colonic distension cycle.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula 1 or 1A or acorresponding pharmaceutically acceptable salt of a compound of Formula1 or 1A.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted, and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 1 g according to the particularapplication and the potency of the active component. In medical use thedrug may be administered three times daily as, for example, capsules of100 or 300 mg. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use, the compounds utilized in the pharmaceutical methodof this invention are administered at the initial dosage of about 0.01mg to about 100 mg/kg daily. A daily dose range of about 0.01 mg toabout 100 mg/kg is preferred. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

General Synthetic Schemes

Compounds

wherein R¹–R¹⁴ may be selected independently from: hydrogen, straight orbranched alkyl of from 1 to 6 carbon atoms, phenyl, benzyl, fluorine,chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl,trifluoromethyl, —OR¹⁵, where R¹⁵ may be straight or branched alkyl offrom 1 to 6 carbon atoms, phenyl or benzyl, —CO₂H, CO₂R¹⁵, —CH₂CO₂H,—CH₂CO₂R¹⁵. R¹–R⁸ may not all be hydrogen can be made by the followingmethods.

Both the 4- and 5-membered ring compounds may be synthesized by theroutes outlined below for the 5-membered ring system. The compoundsclaimed may be synthesized, for example, by utilizing the generalstrategy (General Scheme 1) outlined by G. Griffiths et al., Helv. Chim.Acta, 1991; 74: 309. Alternatively, they may also be made as shown(General Scheme 2), analogously to the published procedure for thesynthesis of 3-oxo-2,8-diazaspiro[4,5]decane-8-carboxylic acidtert-butyl ester (P. W. Smith et al., J. Med. Chem., 1995; 38: 3772).

The compounds may also be synthesized by the methods outlined by G.Satzinger et al., (Ger Offen 2,460,891; U.S. Pat. No. 4,024,175, and GerOffen 2,611,690; U.S. Pat. No. 4,152,326) (General Schemes 3 and 4). Thecompounds may also be synthesized by the route outlined by G. Griffithset al., Helv. Chim. Acta, 1991; 74: 309 (General Scheme 5).

The following examples are illustrative of the instant invention; theyare not intended to limit the scope.

In Examples 1 to 8, the first step involves the conversion of a cyclicketone to an α,β-unsaturated ester 2 via use of atrialkylphosphonoacetate or an(alkoxycarbonylmethyl)triphenylphosphonium halide and a base, such assodium hydride, potassium hydride, lithium- or sodium- orpotassium-hexamethyldisilazide, butyllithium or potassium t-butoxide ina solvent such as tetrahydrofuran, dimethylformamide, diethylether ordimethylsulfoxide at a suitable temperature in the range from −78° C. to100° C.

The second step involves reaction of the α,β-unsaturated ester 2 withnitromethane and a suitable base such as tetrabutylammonium fluoride,tetramethylguanidine, 1,5-diazabicyclo[4,3,0]non-5-ene,1,8-diazabicyclo[5,4,0]undec-7-ene, a sodium or potassium alkoxide,sodium hydride or potassium fluoride in a solvent such astetrahydrofuran, diethylether, dimethylformamide, dimethylsulphoxide,benzene, toluene, dichloromethane, chloroform or tetrachloromethane at asuitable temperature in the range from −20° C. to 100° C.

The third step involves catalytic hydrogenation of the nitro moiety of 3using a catalyst such as Raney nickel, palladium on charcoal or rhodiumcatalyst or other nickel or palladium containing catalyst in a solventsuch as methanol, ethanol, isopropanol, ethyl acetate, acetic acid,1,4-dioxane, chloroform or diethyl ether at a suitable temperature inthe range from 20° C. to 80° C.

The fourth step involves hydrolysis of lactam 4 using hydrochloric acidand may also utilize a co-solvent such tetrahydrofuran or 1,4-dioxane orother such inert water miscible solvent at a suitable temperature in therange from 20° C. to reflux.

EXAMPLE 1

Synthesis of (trans)-(3,4-Dimethyl-cyclopentylidene)-acetic Acid EthylEster (2)

NaH (60% dispersion in oil, 737 mg, 18.42 mmol) was suspended in drytetrahydrofuran (50 mL) and cooled to 0° C. Triethylphosphonoacetate(3.83 mL, 19.30 mmol) was added and the mixture stirred at 0° C. for 15minutes. The ketone (1) (1.965 g, 17.54 mmol) in THF (10 mL) was thenadded and the mixture allowed to warm to room temperature. After 2hours, the mixture was partitioned between diethyl ether (200 mL) andwater (150 mL). The organic phase was separated, washed with brine,dried (MgSO₄) and the solvent removed in vacuo. The residue was purifiedby flash chromatography (silica, ethyl acetate:heptane 1:9) to give 3.01g (94%) of (2) as a colorless oil.

¹H NMR 400 MHz (CDCl₃): δ 1.01 (3H, d, J=6 Hz), 1.03 (3H, d, J=6 Hz),1.26 (3H, t, J=7 Hz), 1.49 (2H, m), 2.07 (1H, m), 2.24 (1H, m), 2.61(1H, m), 4.13 (2H, q, J=7 Hz), 5.72 (1H, s).

MS (CI+) m/e: 183 ([MH⁺], 18%).

Synthesis of (trans)-(3,4-Dimethyl-1-nitromethyl-cyclopentyl)-aceticacid ethyl ester (3)

The unsaturated ester (2) (2.95 g, 16.2 mmol) was dissolved intetrahydrofuran (10 mL) and stirred at 70° C. with nitromethane (1.9 mL,35.2 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 22mL, 22.0 mmol). After 6 hours, the mixture was cooled to roomtemperature, diluted with ethyl acetate (50 mL), and washed with 2N HCl(30 mL) followed by brine (50 mL). The organic phase was collected,dried (MgSO₄) and the solvent removed in vacuo. The residue was purifiedby flash chromatography (silica, ethyl acetate:heptane 1:9) to give1.152 g (29%) of a clear oil.

¹H NMR 400 MHz (CDCl₃): δ 0.98 (6H, d, J=6 Hz), 1.10–1.39 (5H, m), 1.47(2H, m), 1.87 (1H, m), 2.03 (1H, m), 2.57 (2H, ABq, J=16, 38 Hz), 4.14(2H, q, J=7 Hz), 4.61 (2H, ABq, J=12, 60 Hz).

MS (ES+) m/e: 244 ([MH⁺], 8%).

IR (film) ν cm⁻¹: 1186, 1376, 1549, 1732, 2956.

Synthesis of (+)-(trans)-7,8-Dimethyl-2-aza-spiro[4.4]nonan-3-one (4)

The nitroester (3) (1.14 g, 4.7 mmol) was dissolved in methanol (50 mL)and shaken over Raney nickel catalyst under an atmosphere of hydrogen(40 psi) at 30° C. After 5 hours, the catalyst was removed by filtrationthrough celite. The solvent was removed in vacuo to give 746 mg (95%) ofa pale yellow oil which solidified on standing.

¹H NMR 400 MHz (CDCl₃): δ 0.98 (6H, d, J=6 Hz), 1.32 (2H, m), 1.46 (2Hm), 1.97 (2H, m), 2.27 (2H, ABq, J=16, 27 Hz), 3.23 (2H, s), 5.62 (1H,br s).

MS (ES+) m/e: 168 ([MH⁺], 100%).

IR (film) ν cm⁻¹: 1451, 1681, 1715, 2948, 3196.

Synthesis of (±)-(trans)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-aceticAcid Hydrochloride (5)

The lactam (4) (734 mg, 4.40 mmol) was heated to reflux in a mixture of1,4-dioxan (5 mL) and 6N HCl (15 mL). After 4 hours, the mixture wascooled to room temperature, diluted with water (20 mL), and washed withdichloromethane (3×30 mL). The aqueous phase was collected and thesolvent removed in vacuo. The residue was triturated with ethyl acetateto give 675 mg (69%) of a white solid after collection and drying.

¹H NMR 400 MHz (d₆-DMSO): δ 0.91 (6H, d, J=6 Hz), 1.18 (2H, m), 1.42(2H, m), 1.72 (1H, m), 1.87 (1H, m), 2.42 (2H, ABq, J=16, 24 Hz), 2.90(2H, ABq, J=12, 34 Hz), 8.00 (3H, br s), 12.34 (1H, br s).

MS (ES+) m/e: 186 ([MH-HCl]⁺, 100%).

EXAMPLE 2

Synthesis of Cyclobutylidene-acetic Acid Ethyl Ester (2)

NaH (60% dispersion in oil, 1.80 g, 44.94 mmol) was suspended in drytetrahydrofuran (80 mL) and cooled to 0° C. Triethylphosphonoacetate(9.33 mL, 47.08 mmol) was added and the mixture stirred at 0° C. for 15minutes. Cyclobutanone (1) (3.0 g, 42.8 mmol) in THF (20 mL) was thenadded and the mixture allowed to warm to room temperature. After 2hours, the mixture was partitioned between diethyl ether (200 mL) andwater (150 mL). The organic phase was separated, washed with brine,dried (MgSO₄), and the solvent removed in vacuo at 600 mm Hg. Theresidue was purified by flash chromatography (silica, ethylacetate:pentane 1:19) to give 5.81 g (96%) of (2) as a colorless oil.

¹H NMR, 400 MHz (CDCl₃): δ 1.27 (3H, t, J=6 Hz), 2.09 (2H, m), 2.82 (2H,m), 3.15 (2H, m), 4.14 (2H, q, J=6 Hz), 5.58 (1H, s).

MS (ES+) m/e: 141 ([MH⁺], 100%). IR (film) ν cm⁻¹: 1088, 1189, 1336,1673, 1716, 2926.

Synthesis of (1-Nitromethyl-cyclobutyl)-acetic Acid Ethyl Ester (3)

The unsaturated ester (2) (5.79 g, 41.4 mmol) was dissolved intetrahydrofuran (20 mL) and stirred at 70° C. with nitromethane (4.67mL, 86.4 mmol) and tetrabutylammonium fluoride (1.0 M intetrahydrofuran, 55 mL, 55.0 mmol). After 18 hours, the mixture wascooled to room temperature, diluted with ethyl acetate (150 mL), andwashed with 2N HCl (60 mL) followed by brine (100 mL). The organic phasewas collected, dried (MgSO₄), and the solvent removed in vacuo. Theresidue was purified by flash chromatography (silica, ethylacetate:heptane 1:1) to give 4.34 g (52%) of a clear oil.

¹H NMR 400 MHz (CDCl₃): δ 1.27 (3H, t, J=6 Hz), 1.96–2.20 (6H, m), 2.71(2H, s), 4.15 (2H, q, J=6 Hz), 4.71 (2H, s).

MS (ES+) m/e: 202 ([MH⁺], 100%).

IR (film) ν cm⁻¹: 1189, 1378, 1549, 1732, 2984.

Synthesis of (1-Aminomethyl-cyclobutyl)-acetic Acid Hydrochloride (4)

The nitroester (3) (2.095 g, 10.4 mmol) was dissolved in methanol (50mL) and shaken over Raney nickel catalyst under an atmosphere ofhydrogen (45 psi) at 30° C. After 6 hours, the catalyst was removed byfiltration through celite. The solvent was removed in vacuo to give 1.53g of a pale yellow oil which was used without purification. The oil wasdissolved in 1,4-dioxane (5 mL) and 6N HCl (15 mL) and heated to reflux.After 5 hours, the mixture was cooled to room temperature, diluted withwater (20 mL), and washed with dichloromethane (3×30 mL). The aqueousphase was collected and the solvent removed in vacuo. The residue wastriturated with ethyl acetate to give 1.35 g (72%) of a white solidafter collection and drying.

¹H NMR 400 MHz (d₆-DMSO): δ 1.80–2.03 (6H, m), 2.59 (2H, s), 3.02 (2H,s) 8.04 (3H, br s), 12.28 (1H, br s).

MS (ES+) m/e: 144 ([MH-HCl]⁺, 100%).

Microanalysis calculated for C₇H₁₄NO₂Cl: C, 46.80%; H, 7.86%; N, 7.80%.

Found: C, 46.45%; H, 7.98%; N, 7.71%.

EXAMPLE 3

Synthesis of (R)-(3-Methyl-cyclopentylidene)-acetic acid ethyl ester (2)

NaH (60% dispersion in oil, 1.86 g, 46.5 mmol) was suspended in drytetrahydrofuran (40 mL) and cooled to 0° C. Triethylphosphonoacetate(9.69 mL, 48.8 mmol) was added and the mixture stirred at 0° C. for 15minutes. The ketone (1) (5 ml, 46.5 mmol) in THF (10 mL) was then addedand the mixture allowed to warm to room temperature. After 2 hours, themixture was partitioned between diethyl ether (200 mL) and water (150mL). The organic phase was separated, washed with brine, dried (MgSO₄)and the solvent removed in vacuo. The residue was purified by flashchromatography (silica, ethyl acetate:heptane 1:9) to give 5.45 g (70%)of (2) as a colorless oil.

¹H NMR 400 MHz (CDCl₃): δ 1.04 (3H, m), 1.27 (3H, t, J=7 Hz), 1.80–2.74(7H, m), 2.90–3.15 (1H, m), 4.13 (2H, q, J=7 Hz), 5.76 (1H, s).

MS (CI+) m/e: 169 ([MH⁺], 20%).

IR (film) ν cm⁻¹: 1205, 1371, 1653, 1716, 2955.

Synthesis of(cis/trans)-(3R)-(3-Methyl-1-nitromethyl-cyclopentyl)-acetic acid ethylester (3)

The unsaturated ester (2) (3.0 g, 17.8 mmol) was dissolved intetrahydrofuran (20 mL) and stirred at 70° C. with nitromethane (1.92mL, 35.6 mmol) and tetrabutylammonium fluoride (1.0 M intetrahydrofuran, 25 mL, 25.0 mmol). After 18 hours, the mixture wascooled to room temperature, diluted with ethyl acetate (50 mL), andwashed with 2N HCl (30 mL) followed by brine (50 mL). The organic phasewas collected, dried (MgSO₄), and the solvent removed in vacuo. Theresidue was purified by flash chromatography (silica, ethylacetate:heptane 1:9) to give 2.00 g (49%) of a clear oil.

¹H NMR 400 MHz (CDCl₃): δ 1.02 (3H, d, J=6 Hz), 1.08–1.37 (5H, m),1.59–2.17 (5H, m), 2.64 (2H, m), 4.15 (2H, q, J=7 Hz), 4.64 (2H, m).

MS (ES+) m/e: 230 ([MH⁺], 4%).

IR (film) ν cm⁻¹: 1183, 1377, 1548, 1732, 2956.

Synthesis of (cis/trans)-(7R)-7-Methyl-2-aza-spiro[4.4]nonan-3-one (4)

The nitroester (3) (1.98 g, 8.66 mmol) was dissolved in methanol (50 mL)and shaken over Raney nickel catalyst under an atmosphere of hydrogen(40 psi) at 30° C. After 18 hours, the catalyst was removed byfiltration through celite. The solvent was removed in vacuo and theresidue purified by flash chromatography (silica, ethyl acetate:heptane1:1) to give 1.05 g (79%) of a white solid.

¹H NMR 400 MHz (CDCl₃): δ 1.03 (3H, m), 1.22 (2H, m), 1.60–2.15 (5H, m),2.22 (2H, m), 3.20 and 3.27 (2H total, 2×s, cis, and trans), 6.18 (1H,br s).

MS (ES+) m/e: 154 ([MH⁺], 100%).

IR (film) ν cm⁻¹: 1695, 2949, 3231.

Synthesis of(cis/trans)-(3R)-(1-Aminomethyl-3-methyl-cyclopentyl)-acetic AcidHydrochloride (5)

The lactam (4) (746 mg, 4.88 mmol) was heated to reflux in a mixture of1,4-dioxan (5 ntL) and 6N HCl (15 mL). After 4 hours, the mixture wascooled to room temperature, diluted with water (20 mL), and washed withdichloromethane (3×30 mL). The aqueous phase was collected and thesolvent removed in vacuo. The residue was triturated with ethyl acetateto give a white solid which was collected and dried. This wasrecrystallized from ethyl acetate/methanol to give 656 mg (65%) of (5)after collection and drying.

¹H NMR 400 MHz (d₆-DMSO): δ 0.96 (3H, m), 1.01–1.24 (2H, m), 1.42–2.10(5H, m), 2.41 and 2.44 (2H total, 2×s, cis/trans), 2.94 (2H, m), 7.96(3H, br s), 12.35 (1H, br s).

MS (ES+) m/e: 172 ([MH-HCl]⁺, 100%).

EXAMPLE 4

Synthesis of (cis)-(3,4-Dimethyl-cyclopentylidene)-acetic Acid EthylEster (2)

NaH (60% dispersion in oil, 519 mg, 12.96 mmol) was suspended in drytetrahydrofuran (30 nL) and cooled to 0° C. Triethylphosphonoacetate(2.68 mL, 13.5 mmol) was added and the mixture stirred at 0° C. for 15minutes. The ketone (1) (1.21 g, 10.80 mmol) in THF (10 mL) was thenadded and the mixture allowed to warm to room temperature. After 2hours, the mixture was partitioned between diethyl ether (200 mL) andwater (150 mL). The organic phase was separated, washed with brine,dried (MgSO₄) and the solvent removed in vacuo. The residue was purifiedby flash chromatography (silica, ethyl acetate:heptane 5:95) to give1.40 g (71%) of (2) as a colorless oil.

¹H NMR 400 MHz (CDCl 13): δ 0.84 (3H, d, J=6 Hz), 0.91 (3H, d, J=6 Hz),1.26 (3H, t, J=7 Hz), 2.01–2.95 (6H, m), 4.13 (2H, q, J=7 Hz), 5.76 (1H,s).

MS (CI+) m/e: 183 ([MH⁺], 18%).

IR (film) ν cm⁻¹: 1043, 1125, 1200, 1658, 1715, 2959.

Synthesis of (trans)-(3,4-Dimethyl-1-nitromethyl-cyclopentyl)-aceticacid ethyl ester (3)

The unsaturated ester (2) (1.384 g, 7.60 mmol) was dissolved intetrahydrofuran (10 mL) and stirred at 70° C. with nitromethane (0.82mL, 15.2 mmol) and tetrabutylammonium fluoride (1.0M in tetrahydrofuran,11.4 mL, 11.4 mmol). After 6 hours, the mixture was cooled to roomtemperature, diluted with ethyl acetate (50 mL) and washed with 2N HCl(30 mL) followed by brine (50 mL). The organic phase was collected,dried (MgSO₄), and the solvent removed in vacuo. The residue waspurified by flash chromatography (silica, ethyl acetate:heptane 5:95) togive 0.837 g (45%) of a clear oil.

¹H NMR 400 MHz (CDCl₃): δ 0.91 (6H, d, J=6 Hz), 1.21–1.39 (5H, m), 1.98(2H, m), 2.18 (2H, m), 2.64 (2H, s), 4.15 (2H, q, J=7 Hz), 4.61 (2H, s).

MS (ES+) m/e: 244 ([MH⁺], 8%).

IR (film) ν cm⁻¹: 1184, 1377, 1548, 1732, 2961.

Synthesis of (trans)-7,8-Dimethyl-2-aza-spiro[4.4]nonan-3-one (4)

The nitroester (3) (0.83 g, 3.4 mmol) was dissolved in methanol (30 mL)and shaken over Raney nickel catalyst under an atmosphere of hydrogen(40 psi) at 30° C. After 4 hours, the catalyst was removed by filtrationthrough celite. The solvent was removed in vacuo to give 567 mg (99%) ofa pale yellow oil which solidified on standing.

¹H NMR 400 MHz (CDCl₃): δ 0.89 (6H, d, J=6 Hz), 1.38 (2H, m), 1.91 (2Hm), 2.10 (2H, m), 2.32 (2H,s), 3.18 (2H, s), 5.61 (1H, br s). MS (ES+)m/e: 168 ([MH⁺], 100%). IR (film) ν cm⁻¹: 1304, 1450, 1699, 2871, 3186.

Synthesis of (1α,3β,4β)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-aceticacid hydrochloride (5)

The lactam (4) (563 mg, 4.40 mmol) was heated to reflux in a mixture of1,4-dioxan (5 mL) and 6N HCl (15 mL). After 4 hours, the mixture wascooled to room temperature, diluted with water (20 mL), and washed withdichloromethane (3×30 mL). The aqueous phase was collected and thesolvent removed in vacuo. The residue was triturated with ethyl acetateto give a white solid which was collected and dried. This wasrecrystallized from ethyl acetate/methanol to give 440 mg (59%) of (5)after collection and drying.

¹H NMR 400 MHz (d₆-DMSO): δ 0.84 (6H, d, J=6 Hz), 1.21 (2H, m), 1.81(2H, m) m), 2.06 (2H, m), 2.47 (2H, s), 2.89 (2H, s), 7.94 (3H, br s),12.30 (1H, br s). MS (ES+) m/e: 186 ([MH-HCl]⁺, 100%).

EXAMPLE 5

Synthesis of (3-Benzyl-cyclobutylidene)-acetic acid ethyl ester (2)

NaH (60% dispersion in oil, 0.496 g, 12.4 mmol), was suspended in drytetrahydrofuran (40 mL) and cooled to 0° C. Triethylphosphonoacetate(2.58 mL, 13.0 mmol) was added and the mixture stirred at 0° C. for 15minutes. The cyclobutanone (1) (1.89 g, 11.8 mmol) in THF (15 mL) wasthen added and the mixture allowed to warm to room temperature. After 4hours, the mixture was partitoned between diethyl ether (200 mL) andwater (150 mL). The organic phase was separated, washed with brine,dried (MgSO₄), and the solvent removed in vacuo. The residue waspurified by flash chromatography (silica, ethyl acetate:heptane 1:4) togive 2.19 g (81%) of (2) as a colorless oil.

¹H NMR 400 MHz (CDCl₃): δ 1.26 (3H, t, J=6 Hz), 2.55 (1H, m), 2.64–2.95(5H, m), 3.28 (2H, m), 4.14 (2H, q, J=6 Hz), 5.63 (1H, s), 7.10–7.32(5H, m).

MS (ES+) m/e: 231 ([MH⁺], 8%). IR (film) ν cm⁻¹: 1190, 1335, 1675, 1715,2980.

Synthesis of (cis/trans)-(3-Benzyl-1-nitromethyl-cyclobutyl)-acetic acidethyl ester (3)

The unsaturated ester (2) (2.17 g, 9.42 mmol) was dissolved intetrahydrofuran (15 mL) and stirred at 70° C. with nitromethane (1.02mL, 18.8 mmol) and tetrabutylammonium fluoride (1.0 M intetrahydrofuran, 14 mL, 14.0 mmol). After 24 hours, the mixture wascooled to room temperature, diluted with ethyl acetate (150 mL), andwashed with 2N HCl (60 mL) followed by brine (100 mL). The organic phasewas collected, dried (MgSO₄) and the solvent removed in vacuo. Theresidue was purified by flash chromatography (silica, ethylacetate:heptane 1:1) to give 1.55 g (57%) of a clear oil.

¹H NMR 400 MHz (CDCl₃): δ 1.25 (3H, m), 1.86 (2H, m), 2.09–2.33 (2H, m),2.53–2.78 (3H, m), 4.15 (2H, q, J=6 Hz), 4.62 and 4.71 (2H total, 2×s,cis/trans), 7.08–7.34 (5H, m). MS (ES+) m/e: 292 ([MH⁺], 100%). IR(film) ν cm⁻¹: 1185, 1378, 1549, 1732, 2933.

Synthesis of (cis/trans)-(1-Aminomethyl-3-benzyl-cyclobutyl)-acetic acidhydrochloride (4)

The nitroester (3) (1.53 g, 5.25 mmol) was dissolved in methanol (50 mL)and shaken over Raney nickel catalyst under an atmosphere of hydrogen(45 psi) at 30° C. After 5 hours, the catalyst was removed by filtrationthrough celite. The solvent was removed in vacuo to give 1.32 g of apale yellow oil which was used without purification. The oil wasdissolved in 1,4-dioxane (5 mL) and 6N HCl (15 mL) and heated to reflux.After 4 hours, the mixture was cooled to room temperature, diluted withwater (20 mL) and washed with dichloromethane (3×30 mL). The aqueousphase was collected and the solvent removed in vacuo. The residue wastriturated with ethyl acetate to give 0.88 g (62%) of a white solidafter collection and drying.

¹H NMR 400 MHz (d₆-DMSO): δ 1.64 (1H, m), 1.84 (2H, m), 2.07 (1H, m),2.20–2.74 (5H, m), 2.98 and 3.04 (2H total, 2×s, cis/trans), 7.10–7.31(5H, m), 8.00 (3H, br s), 12.28 (1H, br s).

MS (ES+) m/e: 234 ([MH-HCl]⁺, 100%).

EXAMPLE 6

Ketone (1) is known in the literature and can be synthesized by themethods outlined therein: Y. Kato, Chem. Pharm. Bull., 1966; 14:1438–1439 and related references: W. C. M. C. Kokke, F. A. Varkevisser,J. Org. Chem., 1974; 39: 1535; R. Baker, D. C. Billington, N. Eranayake,JCS Chem. Comm., 1981: 1234; K. Furuta, K. Iwanaga, H. Yamamoto, Tet.Lett., 1986; 27: 4507; G. Solladie, O. Lohse, Tet. Asymm., 1993; 4:1547; A. Rosenquist, I. Kvarnstrom, S. C. T. Svensson, B. Classon, B.Samuelsson, Acta Chem. Scand., 1992; 46: 1127; E. J. Corey, W. Su, Tet.Lett., 1988; 29: 3423; D. W. Knight, B. Ojhara, Tet. Lett., 1981; 22:5101.

Synthesis of (trans)-(3,4-Dimethyl-cyclopentylidene)-acetic acid ethylester (2)

To a suspension of sodium hydride (1.3 g, 32.5 mmol) in THF (60 mL)under nitrogen at 0° C. was added triethylphosphonoacetate (6.5 mL, 32.7mmol) over 5 minutes. After stirring for a further 10 minutes, asolution of (1) (approx. 2.68 g, approx. 30 mmol) in THF (2×10 mL) wasadded to the now clear solution and the ice bath removed. After 4 hoursthe reaction was quenched by pouring into water (100 mL) and the mixtureextracted with ether (400 mL). The organic phase was washed withsaturated brine (100 mL), dried and concentrated in vacuo. Columnchromatography (10:1 heptane/ethyl acetate) gave the product as an oil,4.53 g, approx. 100%; 91%.

¹H NMR 400 MHz (CDCl₃): δ 1.01 (3H, d, J=6 Hz), 1.03 (3H, d, J=6 Hz),1.26 (3H, t, J=7 Hz), 1.49 (2H, m), 2.07 (1H, m), 2.24 (1H, m), 2.61(1H, m), 4.13 (2H, q, J=7 Hz), 5.72 (1H, s).

MS (CI+) m/e: 183 ([MH⁺], 21%).

Synthesis of (trans)-(3,4-Dimethyl-1-nitromethyl-cyclopentyl)-aceticacid ethyl ester (3)

To a solution of (2) (4.24 g, 23.3 mmol) in THF (15 mL) was added TBAF(32 mL of a 1 M solution in THF, 32 mmol) followed by nitromethane (3mL) and the reaction heated at 60° C. for 8 hours. After cooling, thereaction mixture was diluted with ethyl acetate (150 mL) and washed with2N HCl (40 mL) then saturated brine (50 mL). Column chromatography (10:1heptane/ethyl acetate) gave the product as an oil, 2.24 g, 40%.

¹H NMR 400 MHz (CDCl₃): δ 0.98 (6H, d, J=6 Hz), 1.10–1.39 (5H, m), 1.47(2H, m), 1.87 (1H, m), 2.03 (1H, m), 2.57 (2H, ABq, J=16, 38 Hz), 4.14(2H, q, J=7 Hz), 4.61 (2H, ABq, J=12, 60 Hz).

MS (ES+) m/e: 244 ([MH⁺], 5%).

IR (film) ν cm⁻¹: 1186, 1376, 1549, 1732, 2956.

Synthesis of (3S,4S)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-aceticacid hydrochloride (6)

A solution of (3) (3.5 g, 14.4 mmol) in methanol (100 mL) in thepresence of Ni sponge was hydrogenated at 30° C. and 50 psi for 4 hours.Filtering off the catalyst and concentrating in vacuo gave a 2:1 mixtureof lactam and aminoester, 2.53 g, calculated as 96%, which was usedwithout purification. This mixture (2.53 g, 13.8 mmol) in dioxane (15mL) and 6N HCl (45 mL) was heated under reflux (oil bath=110° C.) for 4hours. After cooling and diluting with water (60 mL), the mixture waswashed with dichloromethane (3×50 mL) and then concentrated in vacuo.The resulting oil was washed with ethyl acetate then dichloromethane togive a sticky foam which was dried to give the product as a whitepowder, 2.32 g, 76%.

α_(D) (23° C.) (H₂O) (c=1.002)=+28.2°.

¹H NMR 400 MHz (d₆-DMSO): δ 0.91 (6H, d, J=6 Hz), 1.18 (2H, m), 1.42(2H, m), 1.72 (1H, m), 1.87 (1H, m), 2.42 (2H, ABq, J=16, 24 Hz), 2.90(2H, ABq, J=12, 34 Hz), 8.00 (3H, br s), 12.34 (1H, br s).

MS (ES+) m/e: 186 ([MH-HCl]⁺, 100%).

EXAMPLE 7

Ketone (1) is known in the literature and can be synthesized by themethods outlined therein: W. C. M. C. Kokke, F. A. Varkevisser, J. Org.Chem., 1974; 39: 1535; Carnmalm, Ark. Kemi, 1960; 15: 215, 219;Carnmalm, Chem. Ind., 1956: 1093; Linder et al., J. Am. Chem. Soc.,1977; 99: 727, 733; A. E. Greene, F. Charbonnier, Tet. Lett., 1985; 26:5525 and related references: R. Baker, D. C. Billington, N. Eranayake,JCS Chem. Comm., 1981:1234; K. Furuta, K. Iwanaga, H. Yamamoto, Tet.Lett., 1986; 27: 4507; G. Solladie, O. Lohse, Tet. Asymm., 1993; 4:1547; A. Rosenquist, I. Kvarnstrom, S. C. T. Svensson, B. Classon, B.Samuelsson, Acta Chem. Scand., 1992; 46: 1127; E. J. Corey, W. Su, Tet.Lett., 1988; 29: 3423; D. W. Knight, B. Ojhara. Tet. Lett., 1981; 22:5101.

Synthesis of (trans)-(3,4-Dimethyl-cyclopentylidene)-acetic acid ethylester (2)

To a suspension of sodium hydride (0.824 g, 20.6 mmol) in THF (40 mL)under nitrogen at 0° C. was added triethylphosphonoacetate (4.1 mL, 20.7mmol) over 5 minutes. After stirring for a further 10 minutes, asolution of (1) (approx. 2.10 g, approx. 15.8 mmol) in THF (2×10 mL) wasadded to the now clear solution and the ice bath removed. After 4 hours,the reaction was quenched by pouring into water (100 mL) and the mixtureextracted with ether (4×100 mL). The organic phase was washed withsaturated brine (50 mL), dried and concentrated in vacuo. Columnchromatography (10:1 heptane/ethyl acetate) gave the product as an oil,2.643 g, approx. 100%; 91%.

¹H NMR 400 MHz (CDCl₃): δ 1.01 (3H, d, J=6 Hz), 1.03 (3H, d, J=6 Hz),1.26 (3H, t, J=7 Hz), 1.49 (2H, m), 2.07 (1H, m), 2.24 (1H, m), 2.61(1H, m), 4.13 (2H, q, J=7 Hz), 5.72 (1H, s).

MS (CI+) m/e: 183 ([MH⁺], 19%).

Synthesis of (trans)-(3,4-Dimethyl-1-nitromethyl-cyclopentyl)-aceticacid ethyl ester (3)

To a solution of (2) (2.44 g, 13.4 mmol) in THF (12 mL) was added TBAF(18 mL of a 1 M solution in THF, 18 mmol) followed by nitromethane (2mL) and the reaction heated at 60° C. for 4 hours. After cooling, thereaction mixture was diluted with ethyl acetate (250 mL) and washed with2N HCl (50 mL) then saturated brine (50 mL). Column chromatography (10:1heptane/ethyl acetate) gave the product as an oil, 1.351 g, 41%.

¹H NMR 400 MHz (CDCl₃): δ0.98 (6H, d, J=6 Hz), 1.10–1.39 (5H, m), 1.47(2H, m), 1.87 (1H, m), 2.03 (1H, m), 2.57 (2H, ABq, J=16, 38 Hz), 4.14(2H, q, J=7 Hz), 4.61 (2H, ABq, J=12, 60 Hz).

MS (ES+) m/e: 244 ([MH⁺], 12%).

IR (film) ν cm⁻¹: 1186, 1376, 1549, 1732, 2956.

Synthesis of (3R,4R)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-aceticacid hydrochloride (6)

A solution of (3) (1.217 g, 5.0 mmol) in methanol (100 mL) in thepresence of Ni sponge was hydrogenated at 30° C. and 50 psi for 4 hours.Filtering off the catalyst and concentrating in vacuo gave a 3:5 mixtureof lactam and aminoester, 1.00 g, calculated as 100%, which was usedwithout purification. This mixture (1.00 g, 5.0 mmol) in dioxane (10 mL)and 6N HCl (30 mL) was heated under reflux (oil bath=110° C.) for 4hours. After cooling and diluting with water (100 mL), the mixture waswashed with dichloromethane (2×50 mL) and then concentrated in vacuo.The resulting oil was washed with ethyl acetate then dichloromethane togive a sticky foam which was dried to give the product as a whitepowder, 0.532 g, 48%.

α_(D) (23° C.) (H₂O) (c=1.01)=−27.0°.

¹H NMR 400 MHz (d₆-DMSO): δ 0.91 (6H, d, J=6 Hz), 1.18 (2H, m), 1.42 (2Hm), 1.72 (1H, m), 1.87 (1H, m), 2.42 (2H, ABq, J=16, 24 Hz), 2.90 (2H,ABq, J=12, 34 Hz), 8.00 (3H, br s), 12.34 (1H, br s).

MS (ES+) m/e: 186 ([MH-HCl]⁺, 100%).

EXAMPLE 8

Synthesis of the dimethylcyclopentanone 1

3,3-Dimethylcyclopentanone was prepared according to the procedure ofHiegel and Burk, J. Org. Chem., 1973; 38: 3637.

Synthesis of (3,3-Dimethyl-cyclopentylidene)-acetic acid ethyl ester (2)

To a stirred solution of triethylphosphonoacetate (1.84 g, 7.52 mmol) inTHF (20 mL) at 0 C was added sodium hydride (300 mg of a 60% dispersionin oil). After 30 minutes, the ketone 1 (766 mg, 6.84 mmol) in THF (5mL) was added. After 24 hours, the solution was diluted with a saturatedsolution of ammonium chloride and the two phases separated. The aqueousphase was extracted with diethyl ether (3×50 mL) and dried (MgSO₄). Thecombined organic phases were concentrated and flash chromatographed(25:1 hexane/ethyl acetate) to give the ester 2 as an oil, (697 mg,56%).

¹H NMR (400 MHz, CDCl₃): δ5.7 (1H, s), 4.1 (2H, q), 2.8 (1H, t), 2.5(1H, t), 2.2 (1H, s), 1.55 (1H, m), 1.45 (1H, m), 1.2 (3H, t), 1.0 (3H,s), 0.98 (3H, S).

MS (m/z): 183 (MH⁺, 100%), 224 (50%).

Synthesis of (±)-(3,3-Dimethyl-1-nitromethyl-cyclopentyl)-acetic acidethyl ester (3)

Tetrabutylammonium fluoride (5.75 mL of a 1 M solution in THF, 5.75mmol) was added to a solution of the ester 2 (697 mg, 3.83 mmol) andnitromethane (467 mg, 7.66 mmol) in THF (20 mL) and the mixture heatedto 70° C. After 19 hours, nitromethane (233 mg, 1.9 mmol) andtetrabutylammonium fluoride (1.9 mL of a 1 M solution in THF, 1.9 mmol)were added and reflux continued for 7 hours, whereupon the solution wascooled to room temperature, diluted with ethyl acetate (40 mL), andwashed with 2N HCl (20 mL) then brine (20 mL). The organic phase wasdried (MgSO₄) and concentrated. The crude product was flashchromatographed (9:1 hexane/ethyl acetate) to give the nitro ester 3(380 mg, 41%) as an oil.

¹H NMR (400 MHz, CDCl₃): δ 4.62 (1H, d), 4.6 (1H, d), 4.1 (2H, q), 2.6(1H, d), 2.58 (1H, d), 1.8 (1H, m), 1.7 (1H, m), 1.6–1.4 (4H, m), 1.2(3H, t), 0.98 (6H, s).

MS (m/z): 244 (MH⁺, 40%), 198 (100%).

Synthesis of (+)-7,7-Dimethyl-2-aza-spiro[4.4]nonan-3-one (4)

The ester 3 (380 mg, 1.6 mmol) and Raney Nickel (1 g) were suspended inmethanol (75 mL) and shaken under a hydrogen atmosphere for 24 hours.The catalyst was removed by filtration, the filtrate concentrated togive the lactam 4 (246 mg, 94%) as a white solid.

¹H NMR (400 MHz, CD₃OD): δ 3.21 (1H, d), 3.08 (1H, d), 2.24 (1H, d),2.18 (1H, d), 1.7 (2H, m), 1.5–1.4 (4H, m), 0.98 (6H, s).

MS (m/z): 168 (MH⁺, 40%).

Synthesis of (±)-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-acetic acidhydrochloride (5)

The lactam (240 mg, 1.44 mmol) in 6N HCl were heated to reflux for 24hours. The residue was concentrated under reduced pressure andtriturated with ether to give the amino acid 5 as a white solid.

¹H NMR (400 MHz, CD₃OD): δ 2.98 (2H, s), 2.4 (2H, s), 1.5 (2H, m),1.4–1.2 (4H, m), 0.84 (3H, s), 0.84 (3H, s).

MS (m/z): 186 (MH⁺, 100%), 168 (M-NH₃, 20%).

EXAMPLE 9 Synthesis of(cis)-(3R)-(1-Aminomethyl-3-methyl-cyclopentyl)-acetic acidhydrochloride

The monoester 1 was prepared according to the procedure described inTetrahedron: Asymmetry 3, 1992: 431.

In the first step, the ester 1 is hydrogenated using catalysts such asRaney nickel, palladium on charcoal or rhodium catalyst or other nickelor palladium containing catalyst in a solvent such as methanol, ethanol,isopropanol, ethyl acetate, acetic acid, 1,4-dioxane, chloroform ordiethyl ether at a suitable temperature in the range from 20° C. to 80°C.

In the second step, the alcohol 2 is treated with triphenylphosphine,imidazole, and iodine in a solvent such as ether, tetrahydrofuran, oracetonitrile at 0° C. to room temperature to give the iodide 3.

In the third step, the iodide 3 is treated with a suitable reducingagent such as lithium aluminium hydride or lithium borohydride in asolvent such as ether or tetrahydrofuran at temperature between 0° C.and or reflux to give the alcohol 4.

In step four, the alcohol 4 is treated with glyoxylic acid chloride(p-toluenesulfonyl)hydrazone and N,N-dimethylaniline followed bytriethylamine in a solvent such as methylene chloride, chloroform,benzene, or toluene to give the diazoacetate 5.

In the fifth step, the diazoacetate 5 is added to a refluxing solutionor suspension of a suitable rhodium(II) catalyst such as Rh₂(cap)₄,Rh₂(5S-MEOX)₄, Rh₂(5S-MEPY)₄, Rh₂(5R-MEPY)₄, or Rh₂(OAc)₄ in a solventsuch as methylene chloride, benzene, toluene, or 1,2-dichloroethane asdescribed by Doyle and Dyatkin in J. Org. Chem., 1995;60:3035 to givethe spirolactone 6.

In step six, the spirolactone 6 is treated with hydrogen bromide orboron tribromide in methanol or ethanol to give a bromoesterintermediate which is then reacted with ammonia to give the spirolactam7.

In step seven, the spirolactam 7 is treated with hydrochloric acidsolution (6N to 12N) at reflux to which may be added a water miscibleco-solvent such as 1,4-dioxane or tetrahydrofuran to give the amino acid8.

1. A compound selected from:(trans)-(3,4-Dimethyl-cyclopentyldine)-acetic acid ethyl ester;(trans)-(3,4-Dimethyl-1-nitromethyl-cyclopentyl)-acetic acid;(+)-(trans)-7,8-Dimethyl-2-aza-spiro[4.4]nonane-3-one;(1-Nitromethyl-cyclopentyl)-acetic acid ethyl ester;(cic/trans)-(3R)-(3-Methyl-1-nitromethyl-cyclopentyl)-acetic acid ethylester; (cis/trans)-(7R)-7-Methyl-2-aza-spiro[4.4]nonane-3-one;(cis)-(3,4-Dimethyl-cyclopentylidene)-acetic acid ethyl ester;(trans)-3,4-Dimethyl-1-nitromethyl-cyclopentyl)-acetic acid ethyl ester;(trans)-7,8-Dimethyl-2-aza-spiro[4.4]nonane-3-one;(3-Benzyl-cyclopentylidine)-acetic acid ethyl ester;(cis/trans)-(3-Benzyl-1-nitromethyl-cyclopentyl)-acetic acid ethylester; (S,S)-7,8-Dimethyl-2-aza-spiro[4.4]nonane-3-one;(trans)-(7R)-7-Methyl-2-aza-spiro[4.4]nonane-3-one; and(R,R)-7,8-Dimethyl-2-aza-spiro[4.4]nonane-3-one.